This invention relates to N-substituted naphthalenecarboxamides, to pharmaceutical compositions containing such compounds, as well as to their uses and to processes for their preparation. These compounds antagonise the pharmacological actions of the endogenous neuropeptide tachykinins known as neurokinins and are useful whenever such antagonism is desired.
Tachykinins are a family of neuropeptides which share a common C-terminal amino acid sequence. Mammalian tachykinins include substance P (SP), neurokinin A (NKA) and neurokinin B (NKB). In addition there are at least two N-terminally extended forms of NKA designated as neuropeptide Y and neuropeptide K. The tachykinins are distributed widely in the peripheral and central nervous systems. At least three receptor types are known for the three principal tachykinins and based upon their relative selectivities favouring the agonists SP, NKA and NKB, the receptors are classified as NK1 (neurokinin 1), NK2 (neurokinin 2) and NK3 (neurokinin 3) receptors, respectively.
As stated above, SP, NKA and NKB are found within the central nervous system. SP is frequently co-localised with NKA. In the peripheral nervous system. NKA and SP are predominantly located in the endings of capsaicin-sensitive primary afferent neurones. A second major source of tachykinins in the periphery is in neuronal cell bodies of the myenteric and submucous plexuses of the gastrointestinal tract. Other neuronal sources include the neurones innervating the salivary glands and a small proportion of intramural neurones in the urinary bladder. Tachykinin-like immunoreactivity has been demonstrated in several other locations including the endocrine cells of the gut, parenchymal cells in the carotid body, chromaffin cells of the adrenal gland, cells of the anterior pituitary, eosinophils and vascular endothelial cells. Human lymphocytes have also been shown to produce substance P.
An important action of tachykinins is neuronal stimulation which is thought to underlie their actions in the CNS, e.g. the excitation of second-order sensory neurones in the spinal cord, the activation of spinal reflexes and induction of pain, the induction of central neurochemical responses such as stimulation of dopamine metabolism, autonomic responses and modulation of salt and water intake. In the periphery, neuronal stimulation by tachykinins leads to facilitation of transmitter release, e.g. contraction of the guinea-pig ileum is mediated partly by neurogenic mechanisms and partly by direct effects.
Tachykinins modulate neuronal activity in sympathetic ganglia. Tachykinins released from collaterals of primary afferent neurones act as mediators of slow excitatory postsynaptic potentials. Central administration of SP and NKA induce tachycardia and an increase in blood pressure in rats via activation of sympathetic nerve activity.
Tachykinins produce an endothelium-dependent vasodilatation which is measurable in vivo as a transient hypotension following i.v. infusion. The effect is mediated via NK1 receptors located on endothelial cells and is thought to involve the release of nitric oxide. Tachykinin-mediated stimulation of endothelial cells also induces their proliferation, migration and angiogenesis, indicating a possible role in growth and repair. In certain blood vessels tachykinins induce vasoconstriction e.g. via the NK2 and NK3 receptors in the rabbit pulmonary artery and the rat hepatic portal vein respectively.
Smooth muscle contraction mediated by tachykinins appears to be predominantly due to a direct spasmogenic effect on the muscle. The combination of this direct effect with the tachykinin-stimulated release of tachkinins from nerve endings forms the basis for their status as excitatory neurotransmitters in the airways, intestine and urinary tract. In human bronchus, urinary bladder, urethra and colon the NK2 receptor is the mediator of this stimulatory response. Tachykinins can also induce smooth muscle relaxation via a NK1 receptor-mediated stimulation of prostanoid production in airway epithelial cells.
SP, NKA and/or NAB have been implicated in the pathology of numerous diseases including asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, airway reactivity, cough, cold, urticaria, inflammation (including neurogenic inflammation), pain, various pain states (including neuropathic pain, visceral pain, ocular pain), migraine, tension headache, angiogenesis, rheumatoid arthritis, psychoses including depression and anxiety, including major depressive disorders, major depressive disorders with anxiety, cognitive disorders, movement disorder, bipolar disorders, substance use disorders, stress disorders, sleep disorders, motion sickness, panic attacks and social phobia, mania, hypomania, aggressive behaviour, pre-menstrual tension and associated appetite disorders, memory loss, emesis, (including ondansetron-resistance emesis), hypertension, oedema, Huntingdon""s disease, Alzheimer""s disease, schizophrenia, neuronal injury such as stroke, epilepsy, spinal cord disorder, Parkinson""s Disease, gastrointestinal-hypermotility, xe2x80x98gastric asthmaxe2x80x99, gastroesphageal reflux disease, Crohn""s disease, gastric emptying disorders. ulcerative colitis, irritable bowel syndrome, inflammatory bowel syndrome, bladder hypermotility, urinary incontinence, cystitis, obesity, bulimia nervosa, cancer, parathyroid hormone deficiency, bone loss, mammalian hair growth, sexual dysfunction, tardive dyskinesia, renal disorders, skin disorders and itch (for example atopic dermatitis and psoriasis).
Examples of reviews covering the use of tachykinin antagonists in various of these disease conditions are: Maggi, C A., Patacchini, R, Rovero, P and Giachetti, A (1993)) Tachykinin receptors and tachykinin receptor antagonists J Auton, Pharmacol. 13, 23-93; McLean, S. (1996), Nonpeptide antagonists of the NK1 tachykinin receptor Med. Res. Rev. 16, 297-317; Raffa R B, Possible role(s) of neurokinins in CNS development and neurodegenerative or other disorders. Neuroscience and Biobehavioral Reviews. 22(6): 789-813, 1998 October; Holzer P, Implications of tachykinins and calcitonin gene-related peptide in inflammatory bowel disease Digestion. 59(4): 269-83, 1998 July-August; Maggi C A., Tachykinins as peripheral modulators of primary afferent nerves and visceral sensitivity. Pharmacological Research. 36(2): 153-69, 1997 August; Kudlacz E M, Expert Opinion. Invest. Drugs (1998), 7(7), 1055-62; and von Sprecher et al, Drugs (1998), 1(1), 73-91.
The N-substituted naphthalenecarboxamide compounds of the present invention are antagonists of at least one of the tachykinin receptors and are of value in treating implicated disease conditions. In particular the compounds have a high degree of NK1 and/or NK2 receptor antagonist activity. Additionally, by manipulation of the substituents on the naphthalene and piperidine rings of the formula (I) hereinbelow, the ratio of activity at the NK1 and NK2 receptors can be modified, affording compounds that are predominantly active at either NK1 or NK2 receptors, or affording compounds with a balanced activity and, as such, are particularly useful when combined antagonism of both receptors is desired. In particular preferred compounds of the present invention also possess a high degree of NK1 and/or NK2 antagonism upon oral administration.
Accordingly, the present invention provides the compounds of the formula (I): 
wherein:
R is alkyl; R1 is optionally substituted phenyl, 2-oxo-tetrahydro-1(2H)-pyrimidinyl, or 2-oxo-1-piperidinyl;
R2 is hydrogen, alkoxy, alkanoyloxy, alkoxycarbonyl, alkanoylamino, acyl, alkyl, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl where the alkyl groups are the same or different, hydroxy, thioacyl. thiocarbamoyl, N-alkylthiocarbamoyl, or N,N-dialkylthiocarbamoyl where the alkyl groups are the same or different;
X1 and X2 are independently hydrogen or halo, provided that at least one of X1 or X2 is halo; and
R3 R4 R5 and R6 are independently hydrogen, cyano, nitro, trifluoromethoxy, trifluoromethyl, or alkylsulfonyl, provided that at least one of R3, R4, R5, and R6 is not hydrogen;
and pharmaceutically acceptable salts and in vivo hydrolysable precursors thereof.
xe2x80x9cAlkylxe2x80x9d means a saturated aliphatic hydrocarbon group which may be straight or branched and having about 1 to about 20 carbon atoms in the chain, Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain.
Preferred alkyl groups are the lower alkyl groups which are those alkyl groups having from 1 to about 6 carbons, for example C1-6alkyl. xe2x80x9cAcylxe2x80x9d means an alkylcarbonyl group for example C1-6alkanoyl. xe2x80x9cThioacylxe2x80x9d means an alkylthiocarbonyl group for example C1-6alkylthiocarbonyl.
R is alkyl for example C1-6alkyl such as methyl, ethyl or n-propyl. Preferably R is methyl so that in one aspect the present invention provides the compounds of the formula (I) wherein R is methyl and the pharmaceutically acceptable salts thereof. In a further aspect the present invention provides the compounds of the formula (I) wherein R is methyl, R1, X1 and X2 are as hereinabove defined; and R2 is hydrogen, acyl, alkyl, carbamoyl, N-alkylcarbamoyl. N,N-dialkylcarbamoyl, hydroxy, thioacyl, thiocarbamoyl, N-alkylthiocarbamoyl or N,N-dialkylthiocarbamoyl, and the pharmaceutically acceptable salts thereof.
In one aspect R1 is optionally substituted phenyl. Suitable substituents for the phenyl ring include:
alkyl such as C1-6alkyl for example methyl or ethyl; alkylthio such as C1-6alkylthio for example methylthio or ethylthio; alkylsulfinyl such as C1-6alkylsulfinyl for example methylsulfinyl, ethylsulfinyl or propylsulfinyl; alkylsulfonyl such as C1-6alkylsulfonyl for example methylsulfonyl or ethylsulfonyl; hydroxy; alkoxy such as C1-6alkoxy for example methoxy or ethoxy; amino; halo for example fluoro, chloro, bromo or iodo; carboxy; alkoxycarbonyl such as C1-6alkoxycarbonyl for example methoxycarbonyl; nitro; alkylamino such as C1-6alkylamino for example methylamino or ethylamino; di-alkylamino (wherein the alkyl groups may be the same or different) such as di-C1-6alkylamino for example dimethylamino; trifluoromethyl; carbamoyl; alkylcarbamoyl such as C1-6alkylcarbamoyl for example methylcarbamoyl; di-alkylcarbamoyl (wherein the alkyl groups may be the same or different) such as di-C1-6alkylcarbamoyl for example dimethylcarbamoyl; trifluoromethylthio; trifluoromethylsulfinyl; trifluoromethylsulfonyl; alkanesulfonamido such as C1-6alkanesulfonamido for example methanesulfonamido; alkanoyl such as C1-6alkanoyl for example acetyl; succinamido; N-alkoxy, N-alkylamino such as Nxe2x80x94C1-6alkoxy, Nxe2x80x94C1-6alkylamino for example N-methoxy, N-methylamino; alkanoylamino such as C1-6alkanoylamino for example acetamido or propionamido; ureido; alkylureido such as C1-6alkylureido for example methylureido (MeNHCONHxe2x80x94) di-alkylureido such as di-C1-6alkylureido for example dimethylureido; alkylsulfonyloxy such as C1-6alkylsulfonyloxy for example methylsulfonyloxy; 2-oxopyrrolidino; N-oxo-N,N-dialkylamino such as N-oxo-N,N-di-C1-6alkylamino for example N-oxo-N,N-dimethylamino; alkoxycarbonylamino such as C1-6alkoxycarbonylamino for example methoxycarbonylamino; alkoxycarbonylcarbonylamino such as C1-6alkoxycarbonylcarbonylamino for example methoxycarbonylcarbonylamino; alkylcarbamoylalkoxy such as C1-6alkylcarbamoylC1-6alkoxy for example methylcarbamoyl methoxy; dialkylcarbamoylC1-6alkoxy such as di-C1-6 alkylcarbamoylalkoxy for example dimethylcarbamoylmethoxy; and C1-6alkyl for example methyl substituted by any of the hereinabove substituents for example methylsulfinylmethyl.
In one aspect R1 is a phenyl group substituted in the ortho-position and in a preferred aspect the ortho-substituent is C1-6alkylthio for example methylthio; C1-6alkylsulfinyl for example methylsulfinyl, ethylsulfinyl or propylsulfinyl; C1-6alkylsulfonyl for example methylsulfonyl or ethylsulfonyl; trifluoromethylthio; trifluoromethylsulfinyl; C1-6alkanesulfonamido for example methanesulfonamido; C1-6alkanoyl for example acetyl or propionyl; C1-6alkoxycarbonyl for example methoxycarbonyl; succinamido; carbamoyl; C1-6alkylcarbamoyl for example methylcarbamoyl; di-C16alkylcarbamoyl for example dimethylcarbamoyl; hydroxy; C1-6alkoxy, C1-6alkylcarbamoyl for example N-methoxy, N-methylcarbamoyl; C1-6alkanoylamino for example acetylamino; ureido, C1-6alkylureido for example methylureido; di-C1-6alkylureido for example dimethylureido; amino; C1-6alkylamino for example methylamino or ethylamino; di-C1-6alkylamino for example dimethylamino; C1-6alkyl-sulfonyloxy for example methylsulfonyloxy; 2-oxopyrrolidino; N-oxo-N,N-di-C1-6alkylamino for example N-oxo-N,N-dimethylamino; C1-6alkoxycarbonylamino for example methoxycarbonylamino; C1-6alkoxycarbonylcarbonylamino for example methoxycarbonylcarbonylamino; C1-6alkylcarbamoylalkoxy for example methylcarbamoylmethoxy; di-C1-6alkylcarbamoylalkoxy for example dimethylcarbamoylmethoxy; or methylsulfinylmethyl. In addition to the ortho-substituent, the phenyl group may have further substituents.
In a further aspect the ortho-substituent is C1-6alkylthio for example methylthio; C1-6alkylsulfinyl for example methylsulfinyl, ethylsulfinyl or propylsulfinyl; C1-6alkylsulfonyl for example methylsulfonyl or ethylsulfonyl; trifluoromethylthio; trifluoromethylsulfinyl; C1-6alkanesulfonamido for example methanesulfonamido; C1-6alkanoyl for example acetyl or propionyl; C1-6alkoxycarbonyl for example methoxycarbonyl; succinamido; carbamoyl; C1-6alkylcarbamoyl for example methylcarbamoyl; di-C1-6alkylcarbamoyl for example dimethylcarbamoyl; C1-6alkoxy, C1-6alkylcarbamoyl for example N-methoxy, N-methylcarbamoyl; C1-6alkanoylamino for example acetylamino; ureido, C1-6alkylureido for example methylureido; di-C1-6alkylureido for example dimethylureido; amino; C1-6alkylamino for example methylamino or ethylamino; or di-C1-6alkylamino for example dimethylamino. In addition to the ortho-substituent, the phenyl group may have further substituents.
Suitable further substituents, which are optional, for the ortho-substituted phenyl ring include C1-6alkyl for example methyl or ethyl; C1-6alkylthio for example methylthio or ethylthio; C1-6alkylsulfinyl for example methylsulfinyl, ethylsulfinyl or propylsulfinyl; C1-6alkylsulfonyl for example methylsulfonyl or ethylsulfonyl; C1-6alkoxy for example methoxy, ethoxy or propoxy; halo for example bromo, fluoro, chloro or iodo; carboxy; C1-6alkoxycarbonyl for example methoxycarbonyl; C1-6alkanoyl for example acetyl or propionyl; nitro; amino; C1-6alkylamino for example methylamino or ethylamino; di-C1-6alkylamino where the alkyl groups may be the same or different, for example dimethylamino; trifluoromethyl; CF3S(O)x wherein x is 0 to 2, for example trifluoromethylthio, trifluoromethylsulfinyl or trifluoromethylsulfonyl; C1-6alkanoylamino for example acetylamino or propionylamino; C1-6alkylsulphonamido for example methylsulphonamido; ureido; C1-6alkylureido for example methylureido (MeNHCONHxe2x80x94), di-C1-6alkylureido for example dimethylureido (Me2NCONHxe2x80x94); carbamoyl; C1-6alkylcarbamoyl for example methylcarbamoyl; di-C1-6alkylcarbamoyl where the alkyl groups may be the same or different, for example dimethylcarbamoyl; and C1-6alkyl for example methyl substituted by any of the hereinabove substituents. Another suitable further substituent for the ortho-substituted ring is hydroxy.
In one aspect, suitable further substituents for a phenyl group already substituted in the ortho-position are C1-6alkyl, C1-6alkylsulfinyl, C1-6alkylsulfonyl, C1-6alkoxy, amino, halo, carboxy, C1-6alkoxycarbonyl, nitro, Nxe2x80x94C1-6alkylamino, N,N-di-C1-6alkylamino (where the alkyl groups may be the same or different), trifluoromethyl, C1-6alkylthio, carbamoyl, Nxe2x80x94C1-6alkylcarbamoyl and N,N-di-C1-6alkylcarbamoyl (where the alkyl groups may be the same or different), C1-6alkanoyl, C1-6alkanesulfonamido, trifluoromethylthio, trifluoromethylsulfinyl, hydroxy, ureido, C1-6alkylureido and di-C1-6alkylureido. Preferably these further substituents are at the 4-position of the phenyl group.
Preferred values for the ortho-substituent are methylsulfinyl, ethylsulfinyl, propylsulfinyl, methylsulfonyl, trifluoromethylthio, trifluoromethylsulfinyl, methanesulfonamido, acetyl, methoxycarbonyl, succinamido, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, N-methoxy, N-methylcarbamoyl, acetylamino, ureido, methylureido, dimethylureido, amino, methylamino and dimethylamino.
In particular the ortho-substituent is methylsulfinyl, methylsulfonyl, methylureido, dimethylureido, amino, methylamino or dimethylamino. Of these methylsulfinyl is particularly preferred.
Favourably the ortho-substituted phenyl ring is not substituted further or is substituted by up to three optional substituents. In particular the ortho-substituted phenyl ring is not substituted further or is substituted at the 4-position, that is the position para- to the bond with the piperidine ring, so forming a 2, 4-disubstituted phenyl group, preferably a 2-MeSO, 4-substituted phenyl group.
Preferred substituents, if present, for the ortho-substituted phenyl ring, are methyl, methoxy, acetyl, acetylamino, methoxycarbonyl, methanesulfonylamino, methylsulfinyl, methylsulfonyl, trifluoromethyl, trifluoromethylthio, trifluoromethylsulfinyl, bromo. fluoro, chloro, hydroxy, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, methylureido and dimethylureido. In particular these preferred substituents may be at the 4-position of the phenyl ring.
A preferred class of compounds is that wherein R1 is of the formula (Ia): 
wherein Ra is hydrogen, C1-6alkyl, C1-6alkylsulfinyl, C1-6alkylsulfonyl, C1-6alkoxy, amino, halo, carboxy, C1-6alkanoyloxy, nitro, Nxe2x80x94C1-6alkyl amino, di-C1-6alkylamino, trifluoromethyl. C1-6alkylthio, carbamoyl, C1-6alkylcarbamoyl and di-C1-6alkylcarbamoyl; and R2 is hydrogen. More preferably, Ra is hydrogen, C1-6alkoxy for example methoxy or ethoxy, halo for example bromo, chloro or fluoro, C1-6alkylsulfinyl for example methylsulfinyl or carboxy.
In one aspect Ra is hydrogen or C1-6alkoxy.
In another aspect Ra is hydrogen, C1-6alkoxy or halo.
More particularly Ra is hydrogen, methoxy or fluoro.
In a particularly preferred aspect Ra is hydrogen.
In another particularly preferred aspect Ra is methoxy.
The compounds of the invention have a number of chiral centres. It is preferred that the ortho-methylsulfinyl substituent, if present, has the stereochemistry depicted in formula (Ib): 
That is the S-stereochemistry according to the Cahn-Prelog-Ingold sequence rules. Preferred values for R1 are therefore 2(S)-methylsulfinylphenyl and 4-methoxy-2(S)-methylsulfinylphenyl.
In another aspect R1 is 2-oxotetrahydro-1(2H)-pyrimidinyl.
In a further aspect R1 is 2-oxo-1-piperidinyl.
R2 is hydrogen; acyl such as C1-6alkanoyl for example acetyl or propionyl; alkyl such as C1-6alkyl for example methyl or ethyl; carbamoyl; N-alkylcarbamoyl such as C1-6alkylcarbamoyl for example methylcarbamoyl or ethylcarbamoyl; N,N-dialkylcarbamoyl such as di-C1-6alkylcarbamoyl for example dimethylcarbamoyl; hydroxy; thioacyl such as C1-6alkylthiocarbonyl for example methylthiocarbonyl; thiocarbamoyl (NH2CSxe2x80x94); N-alkylthiocarbamoyl such as C1-6alkylthiocarbamoyl for example methylthiocarbamoyl (MeNHCSxe2x80x94); N,N-dialkylthiocarbamoyl such as di-C1-6alkylthiocarbamoyl for example dimethylthiocarbamoyl (Me2NCSxe2x80x94); alkoxy such as C1-6alkoxy for example methoxy or ethoxy; alkanoyloxy such as C1-6 alkanoyloxy for example acetyloxy or propionoxy; alkoxycarbonyl such as C1-6alkoxycarbonyl for example methoxycarbonyl or ethoxycarbonyl; or alkanoylamino such as C1-6alkanoylamino for example acetylamino.
In one aspect R2 is hydrogen, acyl, alkyl, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, hydroxy, thioacyl, thiocarbamoyl. N-alkylthiocarbamoyl or N,N-dialkylthiocarbamoyl.
in a preferred aspect R2 is hydrogen, hydroxy, methoxycarbonyl, methylcarbamoyl or dimethylcarbamoyl. When R1 is optionally substituted phenyl, preferably R2 is hydrogen or hydroxy, most preferably hydrogen. When R1 is 2-oxo-tetrahydro-1-(2H)-pyrimidinyl or 2-oxo-1-piperidinyl, preferably R2 is hydrogen, methoxycarbonyl, methylcarbamoyl or dimethylcarbamoyl. In another aspect when R1 is 2-oxo-tetrahydro-1-(2H)-pyrimidinyl or 2-oxo-1-piperidinyl, R2 is hydrogen or Nxe2x80x94C1-6alkylcarbamoyl for example methylcarbamoyl.
Phxe2x80x94X1, X2 is phenyl mono-or di-substituted by halo. Preferably halo is chloro or fluoro and in particular Phxe2x80x94X1, X2 is 4-chloro, 4-fluoro, 3,4-difluoro or 3,4-dichloro. Of these 3,4-dichloro is most preferred.
R3, R4, R5 and R6 are independently hydrogen, cyano, nitro, trifluoromethoxy, trifluoromethyl or alkylsulfonyl (for example C1-6alkylsulfonyl) with the proviso that at least one of R3-R6 is not hydrogen, Preferably R3 is hydrogen. Preferably R4 is cyano. nitro or methylsulfonyl. Preferably R5 is hydrogen or cyano. Preferably R6 is hydrogen, cyano or nitro.
More preferably R3 and R6 are hydrogen, R4 is cyano or nitro, and R5 is hydrogen or cyano.
Most preferably R3, R5 and R6 are hydrogen and R4 is cyano or nitro, in particular cyano so forming the 3-cyano-naphth-1-y1 group.
The compounds of the present invention possess a number of chiral centres, at xe2x80x94CH(Phxe2x80x94X1, X2)xe2x80x94, and possibly in the optional substituents (for example the MeSOxe2x80x94 substituent) on the phenyl groups if present. The present invention covers all isomers, diastereoisomers, atropisomers and mixtures thereof that antagonise tachykinins.
The preferred configuration at xe2x80x94CH(Phxe2x80x94X1, X2)xe2x80x94 is shown in formula (Ic) hereinbelow: 
A preferred class of compounds is that of the formula (II): 
wherein Ra is hydrogen, C1-6alkoxy, halo, C1-6alkylsulfinyl or carboxy; R3 is hydrogen; R4 is cyano or nitro; R5 is hydrogen or cyano; and R6 is hydrogen. In particular Ra is hydrogen, methoxy or fluoro; R3, R5 and R6 are all hydrogen and R4 is cyano or nitro, preferably cyano.
Particular compounds of this invention include those of the Examples hereinbelow.
Pharmaceutically acceptable salts of the compounds of the formula (I) include those made with inorganic or organic acids which afford a physiologically acceptable anion, such as with, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, sulfamic, para-toluenesulfonic, acetic, citric, lactic, tartaric, malonic, fumaric, maleic, maleic, ethanesulfonic, benzenesulfonic, cyclohexylsulfamic, salicyclic and quinic acids.
In vivo hydrolysable precursors include in vivo hydrolysable esters, amides and carbamates which hydrolyse in the animal (e.g. human) body to produce the parent compound. Such precursors, for example esters, amides and carbamates, can be identified by administering, for example intravenously to a test animal, the compound under test and by subsequently examining the test animal""s body fluids. Suitable in vivo hydrolysable precursors include esters of carboxy (RXOOCxe2x80x94) and of hydroxy (RYCOOxe2x80x94).
In order to use a compound of the formula (I) or a pharmaceutically acceptable salt or an in-vivo hydrolysable precursor thereof for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I) or a pharmaceutically acceptable salt or an in-vivo hydrolysable precursor and pharmaceutically acceptable carrier.
The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation or insufflation. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols or nebulisers for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions.
In addition to the compounds of the present invention the pharmaceutical composition of this invention may also contain, or be co-administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more disease conditions referred to herein.
The pharmaceutical compositions of this invention will normally be administered to humans so that, for example, a daily dose of 0.01 to 25 mg/kg body weight (and preferably of 0.1 to 5 mg/kg body weight) is received. This daily dose may be given in divided doses as necessary, the precise amount of the compound received and the route of administration depending on the weight, age and sex of the patient being treated and on the particular disease condition being treated according to principles known in the art.
Typically unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention. For example a tablet or capsule for oral administration may conveniently contain up to 250 mg (and typically 5 to 100 mg) of a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof. In another example, for administration by inhalation, a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof may be administered in a daily dosage range of 5 to 100 mg, in a single dose or divided into two to four daily doses. In a further example, for administration by intravenous or intramuscular injection or infusion, a sterile solution or suspension containing up to 10% w/w (and typically 5% w/w) of a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof may be used.
Therefore in a further aspect, the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof for use in a method of therapeutic treatment of the human or animal body.
In yet a further aspect the present invention provides a method of treating a disease condition wherein antagonism of at least one tachykinin receptor is beneficial which comprises administering to a patient in need thereof an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof. The present invention also provides the use of a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof in the preparation of a medicament for use in a disease condition wherein antagonism of at least one tachykinin receptor is beneficial. In particular the present invention provides a method of treating a disease condition wherein antagonism of the NK1 and/or NK2 receptors is beneficial.
In particular the present invention provides a method of treating asthma which comprises administering to a patient in need thereof an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof.
In particular the present invention provides a method of treating chronic obstructive pulmonary disease which comprises administering to a patient in need thereof an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof.
In particular the present invention provides a method of treating pain which comprises administering to a patient in need thereof an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof.
In particular the present invention provides a method of treating depression which comprises administering to a patient in need thereof an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof.
In particular the present invention provides a method of treating urinary incontinence which comprises administering to a patient in need thereof an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof.
In another aspect the present invention provides a process for preparing a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable precursor thereof which process comprises:
a) reacting a compound of the formula (III) with a compound of the formula (IV): 
wherein R, R1-R6, X1 and X2 are as hereinbefore defined; and L and L1 are groups such that reductive amination of the compounds of the formulae (III) and (IV) forms a Nxe2x80x94C bond; or
b) reacting a compound of the formula (V) with a compound of the formula (VI): 
wherein R1-R6, R2, X1 and X2 are as hereinbefore defined; and L2 is a leaving group; wherein any other functional group is protected, if necessary, and:
i) removing any protecting groups;
ii) optionally forming a pharmaceutically acceptable salt or in vivo hydrolysable precursor.
Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question, and may be introduced and removed by conventional methods; see for example: Theodora W. Greene et al., Wiley (1991), Protective Groups in Organic Chemistry; J F W McOmie, Plenum Press (1973) and Kocienski, Philip J, Georg Thieme Verlag (1994), Protecting Groups. Methods of removal are chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
It will also be appreciated that certain of the various optional substituents in the compounds of the formula (I) may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes described hereinabove. The reagents and reaction conditions for such procedures are well known in the chemical art.
Pharmaceutically acceptable salts may be prepared from the corresponding acid in conventional manner. Non-pharmaceutically acceptable salts may be useful as intermediates and as such are another aspect of the present invention.
In vivo hydrolysable precursors may be prepared from the corresponding functional derivative in conventional manner at any convenient stage of the synthesis.
It is well known in the art how to prepare optically-active forms (for example by resolution of the racemic form or by synthesis from optically-active starting materials) and how to determine the tachykinin antagonist properties by the standard tests known in the art and those described hereinafter.
The compounds of the formulae (III) and (IV) are reacted under conditions of reductive amination. Typically in the compounds of the formula (III) L is hydrogen.
Typically in the compounds of the formula (IV) L1 is an oxo group so forming an aldehyde moiety (i.e. L1 and the carbon atom to which is joined are OHCxe2x80x94). The reaction is typically performed at a non-extreme temperature, for example 0-100xc2x0 C., suitably ambient temperature in a substantially inert solvent for example methanol or dichloromethane. Typical reducing agents include borohydrides such as sodium cyanoborohydride.
In an alternative, in the compounds of the formula (IV), L1 is a leaving group such as halo for example chloro or bromo or is a sulfonate for example methanesulfonate or p-toluenesulfonate. Such compounds are reacted with compounds of the formula (III) wherein L is hydrogen in the presence of a base.
The compounds of the formula (III) are known or may be prepared in conventional manner. The compounds of the formula (IV) may be prepared in a conventional manner. For example when L1 is oxo, compounds of the formula (IV) may be prepared by oxidising a compound of the formula (VII): 
wherein X1, X2, R and R3-R6 are as hereinbefore described. Suitable oxidation conditions include Swern conditions for example oxidation with oxalyl chloride in the presence of dimethylsulfoxide. The compounds of the formula (IV) wherein L1 is a leaving group may be prepaed in conventional manner from a compound of the formula (VII).
The compounds of the formula (VII) may be prepared, for example by reacting a compound of the formula (VI) with a compound of the formula (VIII): 
wherein R, X1 and X2 are as hereinbefore defined under conventional acylation conditions
The compounds of the formulae (V) and (VI) may be reacted under conventional acylation conditions wherein the compound of formula (VI) is an acid or an activated acid derivative. Typical activated acid derivatives are well known in the literature. They may be formed in situ from the acid or they may be prepared, isolated and subsequently reacted. Typically L2 is chloro thereby forming the acid chloride. Typically the acylation reaction is performed in the presence of a non-nucleophilic base, for example di-isopropylethylamine, in a substantially inert solvent at a non-extreme temperature. The compounds of the formula (V) are known or may be prepared in a conventional manner.
The compounds of the formulae (IV) and (VII) are not only useful intermediates but also have good tachykinin antagonist activity, in particular at the NK1 receptor.
Therefore in another aspect, the present invention provides a compound of the formula (IV) or (VII) or a pharmaceutically salt or in vivo hydrolysable precursor thereof.
More particularly the present invention provides a compound of the formula (IX): 
wherein X1, X2 and R3-R6 are as hereinbefore defined;
R8 is xe2x80x94CHO; xe2x80x94CH2OR10 wherein R10 is hydrogen or an ester thereof or C1-6alkyl; and R9 is hydrogen or a group R as hereinbefore defined;
or a pharmaceutically acceptable salt or in vivo hydrolysable precursor thereof.
Suitably R9 is C1-6alkyl for example methyl.
In one aspect R8 is aldehydo (xe2x80x94CHO) or is a derivative thereof. A suitable derivative is an acetal, for example of the formula (RbO)CH(ORc)xe2x80x94 wherein Rb and Rc are independently selected from C1-6alkyl or together form a C2-4methylene chain thus forming a dioxo ring. More suitably Rb and Rc have the same value and are both methyl or are both ethyl.
In a further aspect R8 is xe2x80x94CH2OR10 wherein R10 is hydrogen or C1-6alkyl. Preferably R10 is hydrogen, methyl or ethyl and in particular R10 is hydrogen. In yet a further aspect R10 may represent an ester forming group for example forming a group of the formula xe2x80x94CH2OCORd wherein Rd is C1-6alkyl for example methyl, aryl for example phenyl or arylC1-6alkyl for example benzyl.
Acetals of xe2x80x94CHO and esters of hydroxymethyl (HOCH2xe2x80x94) may be prepared in standard manner.
Preferred values of X1, X2, R and R3-R6 are as described hereinabove for compounds of the formula (I). Accordingly in the compounds of the formula (IX), preferably xe2x80x94PhX1X2xe2x80x94 is 3,4-dichlorophenyl and R is methyl. A preferred class of compounds is that of the formula (X): 
wherein R8 is xe2x80x94CHO or an acetal thereof such as (CH3O)2CHxe2x80x94; or an ester thereof for example acetoxymethyl, or R8 methoxymethyl or ethoxymethyl; R4 is cyano or nitro; and R5 is hydrogen or cyano. In particular R5 is hydrogen and R4 is cyano or nitro, most preferably cyano, and R8 is xe2x80x94CHO or xe2x80x94CH2OH.
These compounds antagonise the NK1 receptor in particular and therefore are particularly beneficial in treating disease conditions mediated through such receptors, for example depression, anxiety, emesis, pain and other disease conditions identified in the literature.
The compounds of the formulae (IX) and (X) may be formulated and administered as described hereinbefore in relation to the compounds of the formula (I).
The following biological test methods, data and Examples serve to illustrate and further describe the invention.
The utility of a compound of the invention or a pharmaceutically acceptable salt or in vivo hydrolysable precursor thereof (hereinafter, collectively referred to as a xe2x80x9cCompoundxe2x80x9d) may be demonstrated by known tests and by clinical studies.
SP Receptor Binding Assay (Test A)
The ability of a Compound of the invention to antagonize the binding of SP at the NK1 receptor may be demonstrated with an assay using the human NK1 receptor expressed in Mouse Erythroleukemia (MEL) cells. The human NK1 receptor was isolated and characterized as described in: B. Hopkins, et al. xe2x80x9cIsolation and characterization of the human lung NK1 receptor cDNAxe2x80x9d Biochem. Biophys. Res. Comm., 1991, 180, 1110-1117; and the NK1 receptor was expressed in Mouse Erythroleukemia (MEL) cells using a procedure similar to that described in Test B below.
In general, the Compounds of the invention having NK1 antagonist activity which were tested demonstrated statistically significant binding activity in Test A with a Ki of 1 microM or much less typically being measured.
Neurokinin A (NKA) Receptor Binding Assay (Test B)
The ability of a Compound of the invention to antagonize the binding of NKA at the NK2 receptor may be demonstrated with an assay using the human NK2 receptor expressed in Mouse Erythroleukemia (MEL) cells, as described in: Aharony, D., et al. xe2x80x9cIsolation and Pharmacological Characterization of a Hamster Neurokinin A Receptor cDNAxe2x80x9d Molecular Pharmacology, 1994, 45, 9-19.
The selectivity of a Compound for binding at the NK1 and the NK2 receptors may be shown by determining its binding at other receptors using standard assays, for example, one using a tritiated derivative of NKB in a tissue preparation selective for NK3 receptors. In general, the Compounds of the invention having NK2 antagonist activity which were tested demonstrated statistically significant binding activity in Test A and Test B with a Ki of 1 microM or much less typically being measured.
Neurokinin B (NKB) Receptor Binding Assay (Test C)
The ability of a Compound of the invention to antagonise the binding of a selective NKB receptor ligand at the NK3 receptor may be demonstrated with an assay using the human NK3 receptor, cloned from human brain and expressed in Mouse Erythroleukemia (MEL) cells. Human NK3 receptor was expressed in MEL cells with a similar procedure to that described for the human NK2 receptor in: Aharony, D., et al. xe2x80x9cIsolation and Pharmacological Characterization of a Hamster Neurokinin A Receptor cDNAxe2x80x9d Molecular Pharmacology, 1994, 45, 9-19.
The selectivity of a Compound for binding at the NK1 and the NK2 receptors may be shown by determining its binding at other receptors using standard assays, for example, one using a tritiated derivative of NKB in a clonal cells expressing the human NK3 receptors. In general, the Compounds of the invention having NK2 antagonist activity which were tested demonstrated statistically significant binding activity in Test A and Test B with a Ki of 1 microM or much less typically being measured.
Rabbit Pulmonary Artery: NK1 in vitro functional assay (Test D)
The ability of a Compound of the invention to antagonize the action of the agonist Ac-[Arg6, Sar9, Met(O2)11] Substance P (6-11), ASMSP, in a pulmonary tissue may be demonstrated as described in Bialecki et al. Kca channel antagonists reduce NO donor-mediated relaxation of vascular and tracheal smooth muscle. Am. J. Physiol. 268: L152-L159, 1995.
Paired tissue segments of pulmonary artery excised from male New Zealand white rabbits are suspended between stainless steel stirrups for analyses of isometric relaxation under standard conditions in physiological salt solution (PSS) containing indomethacin (5 microM; to block cyclooxygenase) and propranolol (1 microM; to block xcex2 adrenergic receptors).
Initial tension placed on each tissue is 2 grams, which is maintained throughout the 1.0 hour equilibration period. Tissues are washed with PSS at 15 minute intervals. At the 30 and 45 minute wash the following treatments are added: Thiorphan (1 microM; to block E.C.3.4.24.11), ((3R)-3-[(1S)-1-(3,4-Dichlorophenyl)-3-(4-[(R or S)-2-methylsulfinyl-phenyl]-piperidino)propyl]-2-ethyl-2,3-dihydroisoindol-1-one) (0.03 microM; to block NK2 receptors as described in: xe2x80x9cAharony D., et al. Pharmacological Characterization of ZD7944: A Novel, Potent and orally-Active Non-Peptide Neurokinin-A (NK-2) Receptor Antagonist Eur. Respir. J. 12 (Suppl. 12):20S, 1998xe2x80x9d), and the given concentration of the Compound being tested. After equilibration, phenylephrine (3 microM) is added to produce steady-state contraction of the tissue and a dose relaxation curve to ASMSP is constructed. Constructed curves are complete when each tissue fails to relax further for 2 consecutive doses. Papaverine (1 milliM) is then added to obtain a maximum reference relaxation.
For antagonists behaving in a noncompetitive manner, the percent inhibition of relaxation is determined at a given concentration of the antagonist. Percent inhibition is determined when a tested Compound produces a statistically significant reduction of the magnitude of maximum relaxation and is calculated as a percentage of the papaverine reference response For antagonists behaving competitively, potencies are determined by calculating the negative log value of the apparent dissociation constant (pKB) for each concentration tested. Statistical significance is determined when the P value is  less than 0.05 using the Student""s t-test for paired comparisons.
In general, the Compounds of the invention having NK1 antagonist activity which were tested demonstrated statistically significant values of the negative log apparent dissociation constant in Test D with a pKB of 6 or much greater typically being measured.
NK2 in vitro functional assay (Test E)
The ability of a Compound of the invention to antagonize the action of the agonist [xcex2-ala8] NKA (4-10), BANK, in a pulmonary tissue may be demonstrated as described in Bialecki et al. Kca channel antagonists reduce NO donor-mediated relaxation of vascular and tracheal smooth muscle. Am. J. Physiol. 268: L152-L159, 1995xe2x80x9d. Left and right pulmonary arteries are excised from male New Zealand white rabbits. The pulmonary arteries are cut into ring segments and the intimal surface rubbed gently to remove the endothelium. Paired tissue segments of pulmonary artery are suspended between stainless steel stirrups for analyses of isometric tension development under standard conditions in physiological salt solution (PSS) containing indomethacin, (5 microM; to inhibit cyclooxygenase).
Initial tension placed on each tissue is 2 grams, which is maintained throughout the 45 minute equilibration period. Tissues are washed with PSS at 15 minute intervals. After the 45 minute equilibration period, 3xc3x9710xe2x88x922M KCl is applied for 60 minutes to test tissue viability. The tissues are then washed extensively for 30 minutes. The concentration of the Compound being tested is then added for 30 minutes before constructing a cumulative concentration-response curve with BANK. The curve is considered complete when each tissue fails to contract further for 2 consecutively increasing BANK concentrations. BaCl2 (3xc3x9710xe2x88x922M ) is then added to produce a maximum reference contraction.
Percent inhibition is determined when a tested Compound produces a statistically significant reduction in the magnitude of maximum contraction and is calculated as a percentage of the BaCl2 reference response. For antagonists behaving competitively, potencies are determined by calculating the negative log value of the apparent dissociation constant (pKB) for each concentration tested. Statistical significance is determined when the P value is  less than 0.05 using the Student""s t-test for paired comparisons.
In general, the Compounds of the invention having NK2 antagonist activity which were tested demonstrated statistically significant values of the negative log apparent dissociation constant in Test E with a pKB value of 6 or much greater typically being measured. NK1 and NK2 in vivo functional assay (Test F)
The activity of a compound as an antagonist of NK1 and/or NK2 receptors also may be demonstrated in vivo in laboratory animals as described in: Buckner et al. xe2x80x9cDifferential Blockade by Tachykinin NK1 and NK2 Receptor Antagonists of Bronchoconstriction Induced by Direct-Acting Agonists and the Indirect-Acting Mimetics Capsaicin, Serotonin and 2-Methyl-Serotonin in the Anesthetized Guinea Pig.xe2x80x9d J. Pharm. Exp. Ther., 1993, Vol 267(3), pp 1168-1175. The assay is carried out as follows.
Compounds are tested in anesthetized guinea pigs pretreated with i.v. indomethacin (10 mg/kg, 20 min.), propranolol (0.5 mg/kg, 15 min.), and thiorphan (10 mg/kg, 10 min).
Antagonists or vehicle are administered i.v. and orally, 30 and 120 minutes prior to increasing concentrations of agonist, respectively. The agonists used in these studies are ASMSP (Ac-[Arg6, Sar9, Met(O2)11]-SP(6-11)) and BANK (xcex2-ala-8 NKA4-10).
Administered i.v., ASMSP is selective for NK1 receptors, and BANK is selective for NK2 receptors. Maximum response is defined as zero conductance (GL, 1/Rp). ED50 values are calculated (the dose of agonist resulting in a reduction of GL to 50% of baseline), and converted to the negative logarithm (xe2x88x92logED50). The ED50 values, obtained in the presence (P) and absence (A) of antagonist, are used to calculate a Dose Ratio (P/A), an expression of potency. Data are expressed as meanxc2x1SEM and statistical differences were determined using ANOVA/Tukey-Kramer and Student""s t-test, with p less than 0.05 considered statistically significant.
Compounds of the present invention exhibit marked activity in the foregoing tests and are considered useful for the treatment of those diseases in which the NK1 and/or NK2 receptor is implicated, for example, in the treatment of asthma and related conditions.
Results of testing of representative compounds of the present invention by the above methods are presented in the Table I.
Clinical Studies
Because of the range of effects attributable to the actions of SP, NKA and NKB, compounds which are capable of blocking their actions may also be useful as tools for further evaluating the biological actions of other neurotransmitters in the tachykinin family. As a result, another feature of the invention is provided by the use of a compound of Formula I or a salt or precursor thereof as a pharmacological standard for the development and standardization of new disease models or assays for use in developing new therapeutic agents for treating diseases in which SP or NKA are implicated or for assays for their diagnosis.